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The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Published OnlineFirst March 11, 2015; DOI: 10.1158/1535-7163.MCT-14-0849 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses Lisa Christiansson1, Stina Soderlund€ 2,3, Sara Mangsbo1, Henrik Hjorth-Hansen4,5, Martin Hoglund€ 2,3, Berit Markevarn€ 6, Johan Richter7, Leif Stenke8, Satu Mustjoki9, Angelica Loskog1, and Ulla Olsson-Stromberg€ 2,3 Abstract Immune escape mechanisms promote tumor progression (arginase I, myeloperoxidase, IL10) as well as the presence of and are hurdles of cancer immunotherapy. Removing immu- natural killer cells, T cells (na€ve/memory), and stimulatory nosuppressive cells before treatment can enhance efficacy. cytokines (IL12, IFNg,MIG,IP10).Bothimatinibanddasatinib þ À þ Tyrosine kinase inhibitors (TKI) may be of interest to combine decreased the presence of CD11b CD14 CD33 myeloid cells with immunotherapy, as it has been shown that the inhibitor as well as the inhibitory molecules and the remaining myeloid sunitinib reduces myeloid suppressor cells in patients with suppressor cells had an increased CD40 expression. Monocytes renal cell carcinoma and dasatinib promotes expansion also increased CD40 after therapy. Moreover, increased levels of of natural killer–like lymphocytes in chronic myeloid leukemia CD40, IL12, natural killer cells, and experienced T cells were (CML). In this study, the capacity of dasatinib and imatinib noted after TKI initiation. The presence of experienced T cells to reduce myeloid suppressor cells and to induce immunomo- wascorrelatedtoahigherIFNg and MIG plasma concentration. dulation in vivo was investigated ex vivo.SamplesfromCML Taken together, the results demonstrate that both imatinib and patients treated with imatinib (n ¼ 18) or dasatinib (n ¼ 14) dasatinib tilted the immunosuppressive CML tumor milieu within a Nordic clinical trial (clinicalTrials.gov identifier: towards promoting immune stimulation. Hence, imatinib and NCT00852566) were investigated for the presence of dasatinib may be of interest to combine with cancer immuno- þ À þ CD11b CD14 CD33 myeloidcellsandinhibitorymolecules therapy. Mol Cancer Ther; 14(5); 1181–91. Ó2015 AACR. Introduction immune system. It is now recognized that tumor cells avoid destruction by natural killer (NK) cells and T cells by releasing Immunotherapy of cancer has been in the limelight during the immunosuppressive molecules as well as molecules that pro- past few years due to the success of, for example, immunomod- mote the differentiation of myeloid suppressor cells and regu- ulatory antibodies such as ipilimumab (anti-CTLA-4) for malig- latory T cells (Treg). Myeloid suppressor cells are a heteroge- nant melanoma (1). Intense research in tumor immunology has neous group of myeloid cells that are increased in most cancer revealed the interplay between tumor cells, its stroma, and the patients (2). They utilize different mechanisms for suppressing immune responses, including upregulation of the enzyme Argi- 1Department of Immunology, Genetics and Pathology, Science for Life nase 1 (Arg1) leading to inhibition of T cells and other immune Laboratories, Uppsala University, Uppsala, Sweden. 2Department cells (3, 4). Moreover, myeloid suppressor cells can affect the of Medical Sciences, Uppsala University, Uppsala, Sweden. 3Section immune system by induction or recruitment of Tregs (5). Tregs of Hematology, Uppsala University Hospital, Uppsala, Sweden. 4Department of Hematology, St. Olav's Hospital, Trondheim, Norway. modulate the immune system by inhibition of effector T cells as 5Department of Cancer Research and Molecular Medicine, Norwegian well as NK cells, dendritic cells, and B cells (6). Immune evasion University of Science and Technology (NTNU) Trondheim, Norway. hampers antitumor immune reactions and is therefore since 6Department of Hematology, Norrland University Hospital, Umea , 2011 recognized as one of the hallmarks of cancer (7). Thus, Sweden. 7Department of Hematology and Coagulation, Skane University Hospital, Lund, Sweden. 8Department of Hematology, Kar- immune evasion strategies need to be considered during the olinska University Hospital and Karolinska Institute, Stockholm, Swe- development of immunotherapy. 9 den. Hematology Research Unit Helsinki, Department of Medicine, Most immunotherapies in clinical trials are currently used Division of Hematology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. together with a preconditioning strategy to reduce the level of suppressive immune cells. For example, cyclophosphamide given Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). before treatment or metronomic during an extended period of time reduces the presence of Tregs (8). The tyrosine kinase € A. Loskog and U. Olsson-Stromberg contributed equally to this article. inhibitor (TKI) sunitinib used for patients with renal cell carci- Corresponding Author: Angelica Loskog, Uppsala University, Rudbeck Labo- noma was primarily used because of its capacity to inhibit VEGF € ratory C11, Dag Hammarskjolds v 20, Uppsala 75185, Sweden. Phone: 467-3537- signaling but it was soon recognized that hampering myeloid 7161; Fax: 461-8611-0222; E-mail: [email protected] suppressor cells was part of the mechanism of action (9). This doi: 10.1158/1535-7163.MCT-14-0849 inhibition has been linked to the suppression of STAT-3 signaling Ó2015 American Association for Cancer Research. (10) a feature shared also with other TKIs such as imatinib and www.aacrjournals.org 1181 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst March 11, 2015; DOI: 10.1158/1535-7163.MCT-14-0849 Christiansson et al. dasatinib (11, 12). TKIs have been used to treat patients with a-CD40-FITC (clone: HB-14). Some patients and control subjects þ À þ chronic myeloid leukemia (CML), as they target the constitutively had very low levels of CD11b CD14 CD33 myeloid cells, þ active tyrosine kinase bcr/abl present only in the CML tumor cells. thus, for these individuals CD40 expression on the CD11b À þ The TKIs imatinib and dasatinib are both very effective for CD14 CD33 myeloid cells could not be analyzed. NK cells CML treatment and are well tolerated but in some patients, were stained with a-CD3-FITC and a-CD56/CD16-PE NK cell inflammation of unknown origin arises, implicating an effect on cocktail (clones: UCHT-1 and 3G8/MEM-188) and were defined À þ the immune system (13). The high response rate is usually as CD3 CD56/CD16 cells. To exclude dead cells from the þ À þ attributed to a direct effect of TKIs on the malignant cells. analysis of CD11b CD14 CD33 myeloid cells and NK cells, However, both in vitro (14–16) and in vivo (17–19) studies show cells were stained with the LIVE/DEAD Fixable Aqua Dead Cell that TKIs can modulate cells of the immune system, possibly Stain Kit, for 405 nm excitation (Life Technologies), according to affecting antitumor immunity of treated patients. the manufacturer's instructions. Cells that excluded the fluores- In this article, we sought to investigate the capacity of imatinib cent dye were considered live cells. For staining of different T-cell and dasatinib to reduce myeloid suppressor cells and their sup- phenotypes, a-CD3-FITC (clone: UCHT-1), a-CD8-APC (clone: pressive mediators in vivo to further understand their mechanism SK-1, BD Biosciences), a-CD45RA-APC/Cy7 (clone: HI-100), and þ of action in CML as well as to validate their capacity to function as a-CCR7-PerCP/Cy5.5 (clone: G043H7) were used. CD8 na€ve þ þ þ þ þ a preconditioning regimen prior, or during, immunotherapy of T cells were identified as CD3 CD8 CD45RA CCR7 , CD8 þ þ À cancer. memory T cells were identified as CD3 CD8 CD45RA .To exclude dead cells from T-cell phenotype staining, 50 ng 406- Materials and Methods diamidino-2-phenylindole, dihydrochloride (DAPI, Life Tech- Patient and control subject samples nologies) was added to the tubes immediately before acquisition Samples from 32 patients were obtained from the "Random- in the flow cytometer. Cells that did not include DAPI were ized Study Comparing the Effect of Dasatinib and Imatinib considered live cells. Tregs were stained by the surface markers on Malignant Stem Cells in Chronic Myeloid Leukemia a-CD3-PerCP (clone: UCHT-1), a-CD4-FITC (clone: OKT-4), (NordCML006)" (clinicalTrials.gov identifier: NCT00852566). a–CD127-PE (clone: HIL-7R-M21, BD Biosciences) then the In this open labeled study, newly diagnosed chronic phase CML cells were fixed and permeabilized with the FOXP3 Fix/Perm patients were randomized to a starting dose of 100 mg dasatinib buffer set according to the instructions from the manufacturer once daily or 400 mg imatinib once daily. Eighteen patients (BioLegend). After permeabilization and blocking with normal treated with imatinib and 14 patients treated with dasatinib were mouse serum (Cedarlane), intracellular FoxP3 was stained with an a-FoxP3-Alexa Fluor 647 antibody (clone: 206D). Tregs analyzed for immune escape mechanisms and related markers. þ þ À þ Plasma samples were taken at inclusion (pre, n ¼ 27), at one (n ¼ were defined as CD3 CD4 CD127 FoxP3 cells. The isotype 23), three (n ¼ 13), and six (n ¼ 23) months after initiation of the control antibodies IgG1-PE (clone: MOPC-21), IgG1-APC (clone: treatment (PTI). PBMCs were also taken before treatment (n ¼ 30) MOPC-21), IgG2b-brilliant violet 421 (clone: MPC-11), IgG1- and after 1 (n ¼ 31) and 6 (n ¼ 30) months PTI. Samples were FITC (clone: MOPC-21), and IgG1-Alexa Fluor 647 (clone: prepared and cryopreserved at the different study sites and cryo- MOPC-21) were used to identify background staining. All specific preserved samples were shipped to Uppsala, Sweden. The study antibodies and isotype controls were from BioLegend unless was performed according to the declaration of Helsinki and all otherwise stated. Cells were analyzed on LSRII (BD Biosciences) patients gave their written informed consent. The clinical study, and data was evaluated in Flow Jo software from Tree star.
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